title: A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells.
abstract: Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival, and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics.
authors.affiliation: Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Miranda
authors.forename: Ida K
authors.initials: IK
authors.lastname: Nordgren
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Male
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lawrence
authors.forename: Franciane
authors.initials: F
authors.lastname: Hoakwie
authors.forename: Francesco
authors.initials: F
authors.lastname: Cuda
authors.forename: William
authors.initials: W
authors.lastname: Court
authors.forename: Keith R
authors.initials: KR
authors.lastname: Fox
authors.forename: Paul A
authors.initials: PA
authors.lastname: Townsend
authors.forename: Graham K
authors.initials: GK
authors.lastname: Packham
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Ali
authors.initials: A
authors.lastname: Tavassoli
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D061986:MCF-7 Cells; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C497396:ARNT protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010456:Peptides, Cyclic; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator